RESUMEN
Rechargeable aqueous zinc-ion batteries (RAZIBs) show great potential as a competitive candidate for reliable energy storage by virtue of cost-effectiveness, high safety, and environmental friendliness. However, unsatisfactory cycle stability of cathode material impedes the development of high-performance RAZIBs. This study reveals a strategic polyol-mediated process by using glycerol as the solvent for solvothermal reaction. After heat treatment in air, Mn-deficient Mn3O4 spinel (D-Mn3O4) can be obtained with rich Mn valence states (Mn2+/Mn3+/Mn4+), expanded crystal structure, high surface area, and good electrolyte compatability. Compared to well-crystallized Mn3O4, the presence of manganese vacancies in D-Mn3O4 enables lower charge-transfer resistance (86.0 vs 196.5 Ω), reduced activation energy for ion insertion (30.9 vs 50.4 kJ mol-1), and boosted solid-state ion diffusivity (9.45 × 10-12 vs 4.61 × 10-14 cm2 s-1). Therefore, D-Mn3O4 exhibits promising electrochemical performance with high capacity (284 mAh g-1), high specific energy (388.5 Wh kg-1) and stable cycle retention (87% after 200 cyclesat 0.3 A g-1). On the contrary, the well-crystallized Mn3O4 sample suffers from severe capacity fading with only 48% capacity retention. Moreover, the specific energies obtained after 200 cycles are 336.1 and 166.0 Wh kg-1 for D-Mn3O4 and Mn3O4, respectively. The drastic differences between the electrochemical performance of D-Mn3O4 and Mn3O4 manifest that the existing manganese vacancies in Mn3O4 spinel structure enhance energy storage capability.
RESUMEN
The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.
Asunto(s)
Glucólisis/efectos de los fármacos , Fosfofructoquinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Trypanosoma/enzimología , Tripanosomiasis Africana/metabolismo , Tripanosomiasis Africana/parasitología , Enfermedad Aguda , Regulación Alostérica/efectos de los fármacos , Animales , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Estimación de Kaplan-Meier , Ratones , Parásitos/efectos de los fármacos , Fosfofructoquinasas/química , Fosfofructoquinasas/metabolismo , Unión Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Multimerización de Proteína , Relación Estructura-Actividad , Trypanosoma/efectos de los fármacos , Tripanosomiasis Africana/tratamiento farmacológicoRESUMEN
A major challenge in the field of ligand discovery is to identify chemically useful fragments that can be developed into inhibitors of specific protein-protein interactions. Low molecular weight fragments (with molecular weight less than 250 Da) are likely to bind weakly to a protein's surface. Here we use a new virtual screening procedure which uses a combination of similarity searching and docking to identify chemically tractable scaffolds that bind to the p53-interaction site of MDM2. The binding has been verified using capillary electrophoresis which has proven to be an excellent screening method for such small, weakly binding ligands.